The great British physicist Sir Roger Penrose likes to say that the human brain is more complex than our Milky Way Galaxy. Why are we the only species that evolved to have the ability to invent the radio, scan the depths of the cosmos with the Hubble Space Telescope, or detect gravitational waves from a collision of black holes in a remote galaxy two billion years ago?

During evolution, the human genome has undergone subtle changes that underlie the expansion of a particular region of the brain called the neocortex responsible for cognitive functions like speaking and thinking. "This change is tiny on a genomic scale but substantial in its functional and evolutionary consequences – it’s a single base substitution that likely drove brain size evolution and that may have set the stage for what makes humans special,” says Wieland Huttner of the Max Planck Institute.

The neocortex, Latin for "new bark," is our third, newly human brain in terms of evolution. It is what makes possible our judgments and our knowledge of good and evil. It is also the site from which our creativity emerges and home to our sense of self.

The neocortex wrote Carl Sagan in Cosmos, is where "matter is transformed into consciousness." It comprises more than two-thirds of our brain mass. The realm of intuition and critical analysis,–it is the neocortex where we have our ideas and inspirations, where we read and write, where we compose music or do mathematics. "It is the distinction of our species," writes Sagan,"the seat of our humanity. Civilization is the product of the cerebral cortex."

Huttner, MPI-CBG Research Group Leader and Director, and his team have recently shown that the gene ARHGAP11B is key to the regulation of brain size.

This gene is only found in humans and in our closest relatives, the Neanderthals and Denisova-Humans, but not in chimpanzees, as collaborator Svante Pääbo from the Max Planck Institute of Evolutionary Anthropology in Leipzig has shown.

Moreover, ARHGAP11B induces an increase in a specific subpopulation of brain stem cells called basal progenitors, which have been implicated in neocortex expansion, and can trigger folding of the neocortex in mice.

C becomes G – a tiny change that makes a huge difference

The human-specific gene ARHGAP11B arose through a partial duplication of the ubiquitous gene ARHGAP11A approximately five million years ago along the evolutionary lineage leading to Neanderthals, Denisovans, and present-day humans, and after this lineage had segregated from that leading to the chimpanzee.

However, the big leap in neocortex expansion began later, about two million years ago. How, then, could ARHGAP11B possibly be a key player in increasing neocortex size, researchers wondered.

There is more to ARHGAP11B that makes it unique: Not only is the gene as such human-specific, but the protein encoded by the gene contains a sequence of 47 amino acids that is only found in humans and that is due to a shift in the reading frame caused by the absence of 55 nucleotides in the ARHGAP11B messenger RNA.

Wieland Huttner and Marta Florio, PhD student in Huttner’s group, first thought that the absence of these 55 nucleotides would go back to when ARHGAP11B arose by partial gene duplication five million years ago.

This is when they got lost, the researchers assumed. But then they realized, to their astonishment, that the stretch of 55 nucleotides is indeed present in the ARHGAP11B DNA and only disappears when the messenger RNA of ARHGAP11B is produced – they are spliced out. This is triggered by a single C-to-G base substitution in the ARHGAP11B gene. A really tiny change at the molecular level, given that the human genome consists of more than three billion base pairs.

The consequences, however, are not tiny at all: The single mutation leads to eliminating the 55 nucleotides from the ARHGAP11B messenger RNA, which in turn leads to the 47 amino acid sequence in the ARHGAP11B protein that is human-specific – leading to an increase in the abundance of basal progenitors, thought to be key to the evolutionary expansion of the human neocortex.

The C-to-G base substitution in ARHGAP11B probably happened much later than when this gene arose about 5 million years ago, anytime between 1.5 million and 500,000 years ago.

The Dresden researchers wanted to cross-check the significance of this base substitution for the function of the ARHGAP11B protein, and therefore reconstructed an ancestral version of the ARHGAP11B gene as it likely arose approximately 5 million years ago – without the single base pair substitution. Remarkably, when expressed in mice, the ancestral ARHGAP11B protein did not lead to an increase in the abundance of basal progenitors.

The finding that a mere single point mutation may have causally contributed to the expansion of the neocortex is remarkable.

Point mutations are not rare, but in the case of ARHGAP11B its advantages seem to have immediately influenced human evolution.

"The universe could so easily have remained lifeless and simple -just physics and chemistry, just the scattered dust of the cosmic explosion that gave birth to time and space," wrote Richard Dawkins, the famed Oxford evolutionary biologist reflecting on the sheer wonder of the emergence of life on Earth and the evolutionary process in The Ancestor's Tale.

"The fact that it did not -the fact that life evolved out of literally nothing, some 10 billion years after the universe evolved literally out of nothing -is a fact so staggering that I would be mad to attempt words to do it justice. And even that is not the end of the matter. Not only did evolution happen: it eventually led to beings capable of comprehending the process by which they comprehend it."